• To demonstrate an improvement in Disease Control Rate (DCR) with ZACTIMA™ (ZD6474) 300 mg as compared to placebo according to the RECIST [ Time Frame: Complete Response (CR) + Partial Response (PR) + Stable disease (SD) at 6 months ] [ Designated as safety issue: No ]
• To quantify the improvement in Objective Response Rate (ORR) (CR+PR) with ZACTIMA™ (ZD6474) 300 mg as compared to placebo according to the RECIST. [ Time Frame: every 12 weeks ] [ Designated as safety issue: No ]
• To demonstrate an improvement in the Overall Survival (OS) with ZACTIMA™ (ZD6474) as compared to placebo [ Time Frame: Treatment until death ] [ Designated as safety issue: No ]
• To determine the safety and tolerability of ZACTIMA™ (ZD6474) [ Time Frame: Assessed at each visit ] [ Designated as safety issue: No ]

This is a parallel group, randomized, double blind, placebo controlled, multicentre study designed to assess whether ZACTIMA confers an improvement in PFS as compared to placebo in subject with locally advanced or metastatic papillary or follicular thyroid carcinoma failing or unsuitable for radioiodine therapy. The trial should be of a sufficient size so that if ZACTIMA is truly active there is a high probability that it will demonstrate an effect sufficiently promising to warrant a follow-up assessment.

• Subjects will be seen weekly for the first 2 weeks, then again at Week 4, Week 8, and Week 12 after randomization, and every 12 weeks thereafter. Upon disease progression, all subjects (both active and placebo) will be unblinded and given the option to discontinue blinded study treatment and enter follow up and survival, or begin open label ZACTIMA 300 mg treatment. All subjects will be followed to collect survival data until

  • 50% of subjects have died. Subjects who are taking ZACTIMA at the time of study closure and wish to remain on therapy will be allowed to continue for as long as the Investigator feels that they are obtaining clinical benefit, or until they are given another anti-cancer therapy. The safety data from all subjects will be assessed on an ongoing basis, including discontinuation and follow up.
• Radiologic evaluation using RECIST criteria will be performed every 12 weeks (± 2 weeks). All medical images will be centralized assessed at the site and centrally reviewed. Subjects will be evaluated until progression, and will then be followed up for survival, regardless of whether they continue randomized treatment, unless they withdraw consent. Post progression open-label ZACTIMA will be offered at the investigators discretion.
• All subjects must submit a suitable archived tumor sample prior to randomization. In the event that a suitable archived sample is not available within 2 weeks prior to randomization, a fresh tumor sample must be obtained in its place prior to randomization. If a subject undergoes the fresh tumor biopsy procedure, this specimen will satisfy the first optional tumor biopsy submission should they consent to the exploratory part of the study.

• No Intervention: Placebo vandetanib
• Experimental: ZACTIMA™ (ZD6474)

Inclusion Criteria:

• Previously confirmed histological diagnosis of locally advanced or metastatic papillary or follicular thyroid carcinoma, without anaplastic component. Tumor sample available for centralized exploratory analysis.
• Presence of one or more measurable lesions at least 1 cm in the longest diameter by spiral CT scan or 2 cm with conventional techniques.
• Progressive disease following RAI131 or patient unsuitable for RAI131 after surgery.
• Serum TSH<0.5mU/L.

Exclusion Criteria:

• Major surgery within 4 weeks before randomization.
• Prior chemotherapy within the last 4 weeks prior to randomization.
• RAI131 therapy within 3 months in patients with radioiodine uptake.
• Radiation therapy within the last 4 weeks prior to randomization (with the exception of palliative radiotherapy).
• Serum bilirubin >1.5 x the upper limit of reference range (ULRR).
• Creatinine clearance < 30 ml/min (calculated by Cockcroft-Gault formula).
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) greater than 2.5 × ULRR, or greater than 5.0 × ULRR if judged by the investigator to be related to liver metastases.
• Clinically significant cardiovascular event (eg myocardial infarction), superior vena cava [SVC] syndrome, New York Heart Association [NYHA] classification of heart failure >II within 3 months before entry, or presence of cardiac disease that in the opinion of the Investigator increases the risk of ventricular arrhythmia.
• History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia or uncontrolled atrial fibrillation), which is symptomatic or requires treatment (CTCAE grade 3), , or asymptomatic sustained ventricular tachycardia.

Subjects with atrial fibrillation controlled by medication are permitted.

• Congenital long QT syndrome or 1st degree relative with unexplained sudden death under 40 years of age.